Severe lesions of vessels, accompanied or not by an increase in blood pressure, are one of the major long term complications of diabetes mellitus. Several lines of evidence indicate abnormalities in growth of vascular smooth muscle and endothelium in both diabetes and hypertension. Cyclic nucleotides are substances implicated in the mediation of action of many hormones and seem to be involved in the regulation of cell growth. Abnormalities in the synthesis, degradation and action of these nucleotides were demonstrated in diabetes mellitus and hypertension in humans and in experimental animals by several groups, including our own. In addition, several protein factors were recently shown to be able to stimulate the proliferation of vascular smooth muscle. In this project we intend to study the metabolism of cyclic nucleotides in human vascular smooth muscle obtained from patients with diabetes mellitus or hypertension. We will search for abnormalities in the enzymes involved in cyclic nucleotide synthesis (adenylate and guanylate cyclase), degradation (phosphodiesterase) and their target enzymes (protein kinase). Smooth muscle and endothelial cells will be cultured from blood vessels of subjects without any form of cardiovascular disease and from subjects with diabetes or hypertension. The mechanism of growth control in these cells will be studied and the role played by cyclic nucleotides in this control will be investigated. Furthermore, the mechanism of action of platelet growth factor and other circulatory factors on smooth muscle growth will be examined in order to determine if this factor has different properties in patients with diabetes mellitus and hypertension. It is our belief that the research outlined in the present proposal will lead to an increase in our knowledge concerning abnormalities in the regulation of growth of vascular smooth muscle in diabetes mellitus and hypertension. Furthermore, a better understanding of the mechanism of abnormal growth of vascular elements in disease may permit the development of new means of therapy and aid the search for preventative measures.